Caffeine (1,3,7-trimethylxanthine) holds the dubious distinction of being the most widely used psychotropic drug in North America. The methylated purine is most often consumed in colas, teas, chocolates and numerous prescription and non-prescription drugs. Despite the ubiquitous consumption of the drug, we still do not know whether or not the drug is an important contributing "lifestyle" factor in the genesis of malignant disease. In this research proposal, we intend to determine whether or not chronic caffeine consumption by laboratory animals contributes to the genesis and/or progression of mammary gland neoplasias. In this proposed study, we have chosen animal models of human breast cancer which are morphologically and physiologically, representative of the broad spectrum of existing rodent models. These models of the human disease are: 1) carcinogen (DMBA) induced mammary carcinomas in Sprague-Dawley rats and BD2F1 mice; 2) hormone (estrogen and progesterone) induced mammary carcinomas in GR mice and 3) virus induced (spontaneous) mammary carcinomas in nulliparous and multiparous C3H mice. In addition, we intend to examine the potential interaction with caffeine of one more additional "lifestyle" factor, i.e., high levels of dietary fat. It is clear that an elevated level of dietary fat is a potent stimulant of rodent mammary gland tumorigenesis. It is important to determine whether or not chronic caffeine consumption can significantly influence the mammary tumorigenic activities of high fat diets. We will examine the interaction of caffeine and high fat diets on the DMBA induced rat mammary carcinoma model, a model of the human disease that has a number of features which have attracted much research (e.g., hormone responsiveness, ductal origin, ease in which initiation and promotion phases can be separately examined, etc.). If chronic caffeine consumption can be shown to consistently potentiate mammary gland tumorigenesis in the models of human breast cancer to be examined in these studies, then a scientific basis for significant concern will have been provided. The primary impetus for this research proposal was generated by a recent report from our laboratory in which we consistently observed a mild but significant promoting effect by caffeine of rat mammary gland carcinogenesis in vivo.